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1.2.5 Immune-Hypothalamic Feedback Signals
Healthy people and animals show only trace amounts of CTKs in their serum, which is
not sufficient to deliver immune-derived signals to the hypothalamus. Sensory nerves
fulfill this function, as they are stimulated locally by CTKs released in immune organs
and at other sites where immune/inflammatory reactions occur. Sensory nerves trans-
mit information about inflammation and immune reactions to the hypothalamic
para-
ventricular nucleus
(PVN), which is the center regulating ADIM. The vagus was also
shown to have similar capabilities. However, recent results indicate that the vagus con-
tains sensory nerve fibers, which serve as immuno-sensors and transmit information
toward the hypothalamus
[33,39,125]
.
1.2.5.1 Feedback by CTKs
CTKs act on the brain; on nerve terminals; on the pituitary, adrenals, gonads, thyroid,
epithelium, endothelium, leukocytes, and fibroblasts; and more. In fact, the entire
organism uses CTKs to communicate (
Figure 1.1
). On this basis it is possible to sug-
gest that CTKs are able to activate/suppress the major regulatory circuits in the body,
at any level, in case of acute febrile illness.
The stress hormones PRL and GH are elevated soon after LPS injection and dur-
ing the initial phase of stress
[13]
. Subsequently, it was discovered that during acute
stress, both adaptive and INIM functions are significantly boosted within peripheral
tissues, which leads to long-lasting immunity. This was termed the
physiological
stress response
[40]
. The enhancement of adaptive immunity is fully justified in this
case, as both GH and PRL levels are increased; so is the HPA axis, which explains
the augmentation of NATIM.
During acute febrile illness, the concentrations of IL-1, TNF, and IL-6 are
elevated in the serum, which initiates APR. Later, during the course of the disease,
numerous other CTKs will contribute. Additional CTKs that were found to activate
the HPA axis are IL-2, -11, -12, and interferon (IFN)
[13]
. Gp 130 CTKs, such as cil-
iary neurotropic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin, IL-11,
and cardiolipin, potentiated the activation of the HPA axis by IL-1
[39,41]
. Leptin
plays a role in regulation of the gonadotropic axis
[42]
.
The CTKs IL-1, IL-2, and IL-6 stimulate the pituitary release of PRL, whereas
IFN- and endothelin-3 are inhibitory
[43]
. In rats, administration of exogenous
IL-1 stimulated the expression of IL-1 mRNA in the hypothalamus by 99%, but
not that of IL-6. IL-1 also significantly elevated the plasma levels of adrenocortico-
tropic hormone (ACTH), PRL, corticotropin, and cortisol production in the adrenal
glands
[44]
. Rats treated with IFN- for 5 days (10 IU/kg body weight) showed a
43% increase in circulating PRL
[45]
. Two of the most potent cytokines regulating
anterior pituitary cell function are LIF and IL-6, which belong to the CTK family
that uses the common gp130 signal transducer. IL-11 and CNTF exerted a similar
stimulatory effect on GH mRNA expression in somatotropic monolayer cell cul-
tures from acromegalic tumors, but these CTKs had no significant influence on GH
secretion. CNTF stimulates PRL secretion in lactotropic monolayer cell cultures
from patients with prolactinoma. In monolayer cell cultures from normal rat anterior
